rs11568514

Positions:

chr5-132392510-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP3PP5BP4

The NM_003060.4(SLC22A5):c.1345T>G(p.Tyr449Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:7

Conservation

PhyloP100: 4.74

Variant links:

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 links:

SLC22A5 (HGNC:):

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a transmembrane_region Helical; Name=10 (size 20) in uniprot entity OCTN2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_003060.4

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 5-132392510-T-G is Pathogenic according to our data. Variant chr5-132392510-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25420.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=4, Likely_pathogenic=2}. Variant chr5-132392510-T-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.104227066). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.1345T>G	p.Tyr449Asp	missense_variant	8/10	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.1345T>G	p.Tyr449Asp	missense_variant	8/10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00376

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000254

AC:

AN:

251478

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00430

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00108

AC:

165

AN:

152336

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00373

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.00122

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:5Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 26, 2016	The SLC22A5 c.1345T>G (p.Tyr449Asp) variant is a missense variant that has been reported in a total of three individuals with systemic primary carnitine deficiency, including in one who carried the variant in a compound heterozygous state and in one who carried the variant in a heterozygous state with an unidentified second variant. The third individual was heterozygous but also carried a variant in the VLCAD gene, which is associated with very-long-chain acyl-CoA dehydrogenase deficiency, a disease with phenotypic overlap to systemic primary carnitine deficiency (Amat di San Filippo and Longo 2004; Li et al. 2010). The p.Tyr449Asp variant was reported in a heterozygous state in one of 270 ethnically diverse healthy volunteers (Urban et al. 2006) and is reported at a frequency of 0.00605 in the African population of the 1000 Genomes Project. Functional studies in CHO cells (Amat di San Filippo and Longo 2004; Amat di San Filippo et al. 2008) and HEK 293 cells (Urban et al. 2006) indicate the variant impairs carnitine transport, reduces sodium stimulation of the channel, and affects substrate specificity but does not affect membrane localization or the kinetic constant of the channel. Based on the evidence, the p.Tyr449Asp variant is classified as a variant of unknown significance but suspicious for pathogenicity for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2024	Variant summary: SLC22A5 c.1345T>G (p.Tyr449Asp) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00025 vs 0.0046), allowing no conclusion about variant significance. c.1345T>G has been reported in the literature as a non-informative genotype (second allele not specified) and at-least one compound heterozygous genotype in individuals affected with features of Systemic Primary Carnitine Deficiency (e.g, Amat di San Fillippo_2004, Dobrowlski_2005, Frigeni_2017, Li_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Amat di San Fillippo_2004, Urban_2006). The most pronounced variant effect results in 18% of normal carnitine transporter activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 15714519, 28841266, 14665638, 31200524, 20574985, 16931768). ClinVar contains an entry for this variant (Variation ID: 25420). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Mar 30, 2021	• The p.Tyr449Asp variant in the SLC22A5 gene has been previously reported in at least 6 individuals with systemic primary carnitine deficiency (Li et al., 2010; Vockley et al., 2000; Amat di San Filippo et al., 2004; Frigeni et al., 2017; Guevara-Campos et al., 2019). In one individual, this variant was observed in trans with another likely pathogenic/pathogenic variant (p.Leu269Argfs*26); and another individual was homozygous for this variant, consistent with autosomal recessive inheritance (Frigeni et al., 2017; ARUP Primary Carnitine Deficiency and SLC22A5 Database). • The p.Tyr449Asp variant has been identified in 92/24,958 African/African-American chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Functional studies of this variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Amat di San Filippo et al., 2004; Urban et al., 2006; Frigeni et al., 2017). • The p.Tyr449Asp variant is located in the intracellular loop between transmembrane domains 10 and 11 of SLC22A5 (Amat di San Filippo et al., 2004). Other nearby disease-associated variants have been described in this domain, including at least one that has been shown to reduce carnitine transport (Wang et al., 2000). • Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Tyr449Asp variant as likely pathogenic for systemic primary carnitine deficiency in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PS3_moderate; PM3; PM1; PP3] -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 449 of the SLC22A5 protein (p.Tyr449Asp). This variant is present in population databases (rs11568514, gnomAD 0.4%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 28841266; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25420). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 14665638, 16652335, 16931768, 18337137). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -

not provided

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2024	Reported in an individual with 12.4% carnitine transport activity in fibroblasts who also harbored a frameshift variant in SLC22A5, however it is not known whether the two variants occurred on the same (in cis) or opposite (in trans) allele (PMID: 28841266); Reported in two individuals who were heterozygous for this single variant in SLC22A5 (PMID: 15714519, 14665638); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published expression studies are conflicting as to whether the Y449D variant reduces carnitine transport to a level expected to be pathogenic (PMID: 16931768, 14665638); This variant is associated with the following publications: (PMID: 26828774, 18673259, 16602102, 23379544, 14665638, 25087612, 23757202, 20574985, 19940846, 16652335, 18337137, 31200524, 31980526, 32778825, 34637945, 35281663, 16931768, 38166572, 36343260, 15714519, 28841266) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2017	The SLC22A5 c.1345T>G, p.Tyr449Asp variant (rs11568514) has been reported in individuals with primary carnitine deficiency (Amat di San Filippo 2004, Li 2010). Functional characterization of the variant protein indicates a decrease in carnitine transport in response to sodium, and an altered preference for tetraethylammonium cation (Amat di San Filippo 2004, Urban 2006). The p.Tyr449Asp variant is located in the intracellular loop between transmembrane domains 10 and 11, and another alteration in this region (p.Glu452Lys) have also been shown to affect sodium-dependent carnitine transport (Wang 2000), suggesting that this region has functional significance. The variant is listed as pathogenic in ClinVar (Variation ID: 25420), and observed in the general population databases at a frequency of 0.2 percent in the 1000 Genomes Project (8/5008 alleles), 0.1 percent in the Exome Variant Server (16/13006 alleles), and 0.03 percent in the Genome Aggregation Database (90/277216 alleles). The tyrosine at residue 449 is moderately conserved, and computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Amat di San Filippo C et al. Tyrosine residues affecting sodium stimulation of carnitine transport in the OCTN2 carnitine/organic cation transporter. J Biol Chem. 2004; 279(8):7247-53. Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010; 31(8):E1632-51. Urban T et al. Functional genetic diversity in the high-affinity carnitine transporter OCTN2 (SLC22A5). Mol Pharmacol. 2006; 70(5):1602-11. Wang Y et al. Abnormal sodium stimulation of carnitine transport in primary carnitine deficiency. J Biol Chem. 2000; 275(27):20782-6. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 26, 2024	PP3, PM3_supporting, PS3_moderate -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 22, 2021

ACMG classification criteria: PM2, PP3, BP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

D;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.10

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.91

MVP

1.0

MPC

1.1

ClinPred

0.34

GERP RS

6.2

Varity_R

0.97

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over